Antiepileptic drugs potentiating GABA.
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Anticonvulsants↗
Biomedical subjects
B S Meldrum
Publications and source records attributed to B S Meldrum.
The glutamate synapse as a therapeutical target: perspectives for the future.
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Animals↗
Reduction of GABA and glutamate transporter messenger RNAs in the severe-seizure genetically epilepsy-prone rat.
The genetically epilepsy-prone rat is an animal model of inherited generalised tonic-clonic epilepsy that shows abnormal susceptibility to audiogenic seizures and a lowered threshold to a variety of seizure-inducing stimuli. Recent studies suggest a crucial role for glutamate and GABA transporters in epileptogenesis and seizure propagation. The present study examines the levels of expression of the messenger RNAs encoding the glial and neuronal glutamate transporters, GLT-1 and EAAC-1, and the neuronal GABA transporter, GAT-1, in paired male genetically epileptic-prone rats and Sprague Dawley control rats using the technique of in situ hybridization. In a parallel study, semiquantitative immunoblotting was used to assess GLT-1 and EAAC-1 protein levels in similarly paired animals. Animals were assessed for susceptibility to audiogenic seizures on six occasions, and killed seven days following the last audiogenic stimulus exposure. Rat brains were processed for in situ hybridization with radioactive 35S-labelled oligonucleotide probes (EAAC-1 and GAT-1), 35S-labelled riboprobes (GLT-1), and Fluorescein-labelled riboprobes (GLT-1 and GAT-1) or processed for immunoblotting using subtype-specific antibodies for GLT-1 and EAAC-1. Semiquantitative analyses were carried out on X-ray film autoradiograms in several brain regions for both in situ hybridization and immunoblotting studies. Reductions in GAT-1 messenger RNA were found in genetically epileptic-prone rats in all brain regions examined (-8 to -24% compared to control). Similar reductions in GLT-1 messenger RNA expression levels were seen in cortex, striatum, and CA1 (-8 to -12%) of genetically epileptic-prone rats; the largest reduction observed was in the inferior colliculus (-20%). There was a tendency for a reduced expression of EAAC-1 messenger RNA in most regions of the genetically epileptic-prone rat brain although this reached statistical significance only in the striatum (-12%). In contrast, no significant differences in GLT-1 and EAAC-1 protein between genetically epileptic-prone rats and control animals were observed in any region examined, although there was a tendency to follow the changes seen with the corresponding messenger RNAs. These results show differences in the messenger RNA expression levels of three crucial amino acid transporters. For the two glutamate transporters, GLT-1 and EAAC-1, differences in messenger RNA levels are not reflected or are only partially reflected in the expression of the corresponding proteins.
ATP-Binding Cassette Transporters↗
Cerebroprotective effect of the nitric oxide synthase inhibitors, 1-(2-trifluoromethylphenyl) imidazole and 7-nitro indazole, after transient focal cerebral ischemia in the rat.
The novel neuronal nitric oxide synthase inhibitors, 1-(2-trifluoromethylphenyl)imidazole (TRIM) and 7-nitro indazole (7-NI), were used to investigate the role of nitric oxide in a model of transient focal cerebral ischemia in vivo. In halothane-anesthetized rats, the middle cerebral artery (MCA) was occluded for 2 hours using an intravascular thread and then reperfused for 22 hours before histologic evaluation. TRIM (10, 20, or 50 mg/kg), 7-NI (60 mg/kg), TRIM (50 mg/kg) plus L-arginine (300 mg/kg), or L-arginine (300 mg/kg) alone was administered intraperitoneally, either at 5 or 90 minutes after MCA occlusion. Immediate administration (5 minutes after MCA occlusion) of TRIM produced a dose-related reduction in lesion size, which was reversed with L-arginine coadministration. Similarly, delayed administration of TRIM (90 minutes after MCA occlusion, 50 mg/kg) decreased total lesion volume by 48.4% +/- 13.0% in comparison to a reduction of 39.3% +/- 10.9% when TRIM (50 mg/kg) was administered immediately (5 minutes) after occlusion. 7-NI (60 mg/kg) reduced the total lesion volume by 38.5% +/- 13.7% when administered immediately (5 minutes) after MCA occlusion, but had no effect when administration was delayed (90 minutes). Neither TRIM (50 mg/kg) nor 7-NI (60 mg/kg), administered 5 minutes after MCA occlusion, had any significant effect on mean arterial blood pressure throughout the ischemic period or for up to 10 minutes after reperfusion. These results indicate that immediate or delayed administration of the selective neuronal NOS inhibitor TRIM reduces the lesion volume after transient MCA occlusion. In contrast, only immediate administration of 7-NI reduces lesion volume.
Animals↗
Prolonged anticonvulsant action of glutamate metabotropic receptor agonists in inferior colliculus of genetically epilepsy-prone rats.
The anticonvulsant activity of (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG) (an antagonist of Group I and an agonist of Group II metabotropic glutamate (mGlu) receptors), of (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3S)-ACPD) (an agonist of Group II mGlu receptors), and of L-serine-O-phosphate (an agonist of Group III mGlu receptors) was studied against sound-induced seizures in genetically epilepsy-prone (GEP) rats following bilateral microinjection into the inferior colliculus. All 3 drugs produce dose-dependent suppression of all phases of sound-induced seizures (wild running, clonic and tonic). (S)-4C3HPG produces an immediate and short-lasting (< 2 h) protection against sound-induced seizures with an ED50 value of 4.3 (3.2-5.7) nmol, at 5 min. The preferential agonists of Group II and Group III mGlu receptors produce an immediate, transient (< 10 min) proconvulsant effect followed by a prolonged (> 1 day) anticonvulsant effect against sound-induced seizures. The anticonvulsant ED50 value for (1S,3S)-ACPD is 9 (5-18) nmol at 2 h, and for L-serine-O-phosphate is 36 (6.5-199) nmol at 2 days. It is concluded that mGlu receptor activation potently modifies seizure threshold.
Animals↗
The vital dye Evans blue mimics limbic seizures induced by kainate or pilocarpine.
Evans blue dye, given i.c.v. in rats in a dose of 208 nmol, causes electrical and behavioural seizures which resemble those induced by the glutamate analogue, kainate, or by electrical kindling of the amygdala. Chicago sky blue, 201 nmol i.c.v., produces similar seizures. The principal elements of the seizures are wet-rat-shakes, facial and forelimb clonus, rearing and spike-and-waves in the EEG. A non-NMDA receptor antagonist, GYKI 52466 and a benzodiazepine, diazepam, significantly delay the onset to the occurrence of the first forelimb clonus. The cholinergic antagonist, scopolamine, significantly reduces the delay to onset of first facial clonus. The competitive NMDA receptor antagonist, D-CPPene, the non-specific dopamine antagonist, haloperidol, and the purinergic agonist, 2-chloroadenosine, have no effect on the measured parameters. During the induction of seizures by Evans blue, the average extracellular glutamate concentration in hippocampus or cortex does not increase statistically significantly in comparison to pre-seizure values. Histological examination of limbic areas indicates that the moderate to severe Evans blue-induced cell damage is similar to that seen after limbic seizures induced by pilocarpine and in the hippocampus is partially preventable by D-CPPene but not by diazepam or GYKI 52466. It is proposed that Evans blue-induced seizures may be useful as a new model for studying the mechanisms of intractable epilepsy of the complex partial seizure type.
Animals↗
Long-term beneficial effects of BW619C89 on neurological deficit, cognitive deficit and brain damage after middle cerebral artery occlusion in the rat.
4-Amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine (BW619C89) is a sodium channel antagonist which when administered parenterally reduces neurological deficit and infarct volume after middle cerebral artery occlusion in rats. We have investigated whether BW619C89 administered orally before middle cerebral artery occlusion is cerebroprotective when rats are assessed at one day after stroke, and whether cerebroprotection is long lasting and related to functional recovery. A cerebroprotective oral dose of BW619C89 (20 mg/kg) was used to determine whether reduction in infarct volume is long lasting and can be enhanced with continued therapy, and whether behavioural deficits occurring after middle cerebral artery occlusion such as disturbances in cognition and motor coordination are ameliorated by treatment with BW619C89. Rats received sham surgery or middle cerebral artery occlusion with a single treatment of BW619C89 (20 mg/kg) 1 h before middle cerebral artery occlusion, a double treatment group receiving 20 mg/kg BW619C89 1 h before and 10 mg/kg 5 h after middle cerebral artery occlusion, or continued treatment with BW619C89 for up to five days. Neurological deficit, assessed from days 1 to 21, and at 70 days after middle cerebral artery occlusion, was reduced to a similar extent in all three groups of rats treated with BW619C89, compared with vehicle-treated controls. At 70 days after middle cerebral artery occlusion, all groups performed at control level. Vehicle-treated rats were impaired in the Morris water maze and step-through passive avoidance paradigm five to eight weeks after middle cerebral artery occlusion, when neurological deficit was minimal. These deficits were partially alleviated, to a similar extent, by all of the three treatments with BW619C89. Total volumes of brain damage, assessed at 70 days after middle cerebral artery occlusion in Luxol Fast Blue- and Cresyl Violet-stained coronal sections, were reduced in all three groups of BW619C89-treated rats, to 46% in the single, 50% in the double and 58% in the continued treatment group, compared with vehicle-treated rats. Extent of brain damage correlated with extent of impairment of the rats in the water maze. These findings suggest that BW619C89 has long-lasting cerebroprotective effects with advantageous functional consequences after single oral administration in a rodent model of stroke. Prolonged treatment with BW619C89 did not significantly enhance the cerebroprotective effects. Deficits in performance of rats in the water maze and step-through passive avoidance tasks indicate sustained cognitive impairment after middle cerebral artery occlusion. The reductions in brain damage by BW619C89 correlated with significant long-term functional improvement.
Animals↗
Expression of glial glutamate transporters GLT-1 and GLAST is unchanged in the hippocampus in fully kindled rats.
In situ hybridization techniques and quantitative western blotting were used to study the expression of the glial glutamate transporter GLT-1 and GLAST in the brains of normal (implanted, non-kindled) and fully kindled rats. Wistar rats were implanted with stimulating electrodes in the basolateral amygdala, and killed 28 days after the stimulated group had shown stage 5 seizures on five occasions. The brains were processed for in situ hybridization of messenger RNA for GLT-1 using 35S-labelled oligonucleotide probes or digoxigenin-labelled riboprobes. Paired (kindled and non-kindled) sections were used for qualitative and quantitative analyses. Image analysis of autoradiograms showed no change in expression of GLT-1 messenger RNA in any region of the hippocampus or in the cortex. An increase in expression of GLT-1 messenger RNA (expressed as percentage difference of control) was observed bilaterally in the striatum in kindled animals (16-21%, P<0.05). Nuclear emulsion-dipped sections showed predominant glial cell labelling in the hippocampus. Particle density analysis revealed reduced cell labelling in some kindled vs control pairs but overall there was no significant reduction in labelling in CA1. Equivalent results were found in CA1 using digoxigenin-labelled riboprobes. Quantitative immunoblotting also revealed no change in GLT-1 or GLAST transporter protein in the hippocampus of kindled animals. From these data we conclude that the enduring seizure susceptibility associated with the fully kindled state is unlikely to involve alterations in hippocampal GLT-1 messenger RNA or GLT-1 and GLAST transporter protein expression.
ATP-Binding Cassette Transporters↗
Identification and preclinical testing of novel antiepileptic compounds.
Procedures for identifying novel antiepileptic drugs (AEDs) are changing and need to change more. Widespread reliance on two primary screens has led to the identification of novel compounds that resemble either phenytoin (suppressing high-frequency repetitive firing in cultured neurons and prolonging inactivation of voltage-dependent sodium channels identified by the maximal electroshock test) or benzodiazepines (potentiating the inhibitory effect of gamma-aminobutyric acid (GABA), identified by the threshold pentylenetetrazol test). Advances in molecular neurobiology have identified specific molecular targets (subunits of ion channels, neurotransmitter receptors, and transporters) and have made them available in a form permitting high-throughput screening. AEDs can be designed to interact with specific sites on the target molecules. Alternatively, the molecular screens can be used to identify active components in natural products, including folk remedies. Preclinical in vivo screens can be improved by using animals with genetic or acquired epilepsies that have similar modifications in the properties of the target molecules as do human epilepsy syndromes. Future work is likely to define molecular targets for AEDs that will block or reverse chronic epileptogenesis.
Adenosine Triphosphatases↗
First Alfred Meyer Memorial Lecture. Epileptic brain damage: a consequence and a cause of seizures.
Alfred Meyer and his colleagues were the first to report (1954-1956) that the most frequent pathology in tissue from patients with complex partial seizures successfully treated by anterior temporal lobectomy is mesial temporal sclerosis, and that the majority of patients with this lesion give a history of a prolonged seizure early in life. These observations have been repeatedly confirmed. Experimental data from animal models strongly supports the hypothesis that a prolonged generalized or limbic seizure in early life damages the hippocampus and other limbic structures, facilitating an epileptogenic process that, after a latent period, gives rise to spontaneous limbic seizures. Some mechanisms potentially contributing to this process have been identified.
Animals↗
Altered expression of group I metabotropic glutamate receptors in the hippocampus of amygdala-kindled rats.
Kindling is a well documented model of acquired focal epilepsy and synaptic plasticity in the nervous system. Previous biochemical studies have indicated an increase in mGluR-mediated phosphoinositide hydrolysis in the amygdala or hippocampus of fully kindled animals. In this study we have used in situ hybridisation techniques to examine the mRNA expression of group I metabotropic glutamate receptors (mGluR1 and mGluR5 both linked to phosphoinositide hydrolysis) in the hippocampus of amygdala-kindled animals sacrificed 24 h, 7 days or 28 days following the last electrically evoked stage 5 seizure, and in implanted non-stimulated control rats. Results indicate an initial up-regulation in mGluR1 mRNA (expressed as percentage of control) bilaterally in the DG (35-40%) and CA3 (16-48%), and unilaterally in CA4 (12%) in the 24 h post-kindled group. In kindled animals studied 7 days after the last seizure, these changes were either reduced or had returned to control levels. By 28 days mGluR1 mRNA levels had returned to control levels, with only a persistent increase in expression unilaterally in the DG (14%). In contrast, an initial down-regulation in mGluR5 mRNA was observed bilaterally in CA4 (-45 and -25%) and CA1 (-46 and -45%), and unilaterally in DG and CA3 (-27 and -42% respectively) 24 h after the last kindled seizure. In the 7 and 28 day kindled groups significant alterations in expression of mGluR5 mRNA were still apparent. These data show that the mRNAs for mGluR1 and mGluR5 are differentially regulated by kindling, indicating that the expression of each of these receptors is under independent regulatory control. These perturbations in mRNA expression may contribute to kindling epileptogenesis but are unlikely to account for the maintenance of the kindled state.
Amygdala↗
Convulsant and anticonvulsant actions of agonists and antagonists of group III mGluRs.
Group III metabotropic glutamate receptors (mGluR4, 6, 7, 8) are negatively coupled to adenylate cyclase and, when activated presynaptically, decrease the release of glutamate and GABA. We have used intracerebroventricular injections of agonists and antagonists believed to act selectively on these receptors to study the pro- or anti-convulsant effects of mGluR III activation in nonepileptic (Swiss-Webster) and epileptic (DBA/2) mice. In both mouse strains the prototypic agonists L-2-amino-4-phosphonobutanoate (LAP4) and L-serine-O-phosphate are proconvulsant. The supposed antagonists (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), have a predominantly proconvulsant effect. (S)-alpha-methyl-3-carboxyphenylalanine, which is a potent and selective antagonist for LAP4 in the cortex, is anticonvulsant in DBA/2 mice and decreases the convulsant effect of N-methyl-D-aspartate, 3,5-dihydroxyphenylglycine, LAP4 and MPPG in Swiss-Webster mice. These data suggest that reduced inhibitory transmission may be more significant than reduced synaptic release of glutamate following group III mGluR activation.
Acoustic Stimulation↗
Contrasting effects of fetal CA1 and CA3 hippocampal grafts on deficits in spatial learning and working memory induced by global cerebral ischaemia in rats.
Functional effects of fetal hippocampal field grafts were assessed in rats with spatial learning and memory impairments following global cerebral ischaemia. Experiment 1 examined effects of grafts dissected from fields CA1 and CA3 at embryonic day 19 and from the dentate gyrus at postnatal day 1. Cell suspensions (15,000 cells/site) were implanted bilaterally at two points above the dorsal CA1 area two weeks after four-vessel occlusion (electrocoagulation of the vertebral arteries followed the 24 h later by occlusion of the carotid arteries for 15 min). Histological examination showed that CA1 neuronal loss (60-70%) was equivalent in all ischaemic groups and that 80% of CA1 and 60% of CA3 grafts survived and were sited appropriately in the alveus or corpus callosum above the area of ischaemic CA1 damage in the host, but there was no survival of dentate grafts. Results from rats with poor pyramidal cell graft survival were excluded, but those from rats with non-surviving dentate grafts were retained as an additional control group. Acquisition in the water maze was examined nine and 25 weeks after transplantation, and spatial working memory was assessed in three-door runway and water maze matching-to-position tasks 19 and 28 weeks after grafting, respectively. For water maze acquisition rats were trained with two trails/day and a 10 min inter-trial interval for 10-12 days to locate a submerged platform. Ischaemic rats with CA1 grafts learned the platform position as rapidly as non-ischaemic controls, searched appropriately in the training quadrant and were accurate in heading towards the platform, but were initially impaired on recall of the precise platform position on probe trials with the platform removed. Performance of ischaemic controls and groups with CA3 and non-surviving dentate graft groups was significantly impaired relative to controls and to the CA1 grafted group. The CA1 grafted group was also as successful as controls in matching-to-position in the water maze and substantially superior to the other ischaemic groups, assessed using three trials/day, with a 30-s inter-trial interval and a different platform position on each day. In a more complex matching-to-position task in the three-door runway, the performance of the CA1 grafted group was significantly impaired relative to controls, although superior to that of the other ischaemic control and graft groups. Functional recovery with CA1, but not CA3, grafts in ischaemic rats was replicated in a second experiment which assessed water maze acquisition and working memory at 10 and 14 weeks after transplantation, in rats with 90% graft survival. These results indicate that long-lasting, task-dependent improvements can be seen in ischaemic rats with CA1 fetal grafts in both aversively and appetitively motivated spatial learning tasks. The findings suggest that functional recovery requires homotypic replacement of CA1 cells damaged by ischaemia, rather than provision of structurally similar glutamate-releasing CA3 pyramidal cells.
Animals↗
Anticonvulsant effect of reduced NMDA receptor expression in audiogenic DBA/2 mice.
Pretreatment of DBA/2 mice (n = 14-15 per group) with an 18-mer antisense probe to the NMDA-receptor submit NR1 (2 x 1 micrograms, or 2 x 83 pmol, NR1 antisense probe intracerebroventricularly, -29 and -7 h before testing for seizure response) resulted in almost complete suppression of sound-induced clonic seizures. A saline-treated group gave a 100% seizures response, while the group treated with NR1 antisense probe gave a 7% seizure response to the sound stimulus. The group treated with NR1 nonsense-probe showed no anticonvulsant protection (93% seizure response). The anticonvulsant protection observed following NR1 antisense administration was of relatively short duration, with seizure response gradually returning to control levels 12 to 24 h following the termination of antisense administration. When NR1 receptor levels were assessed by receptor autoradiography ([3H]-MK 801 and -CGP 39653 binding) in the same groups of mice, significant (20%) reductions in NR1 levels were observed in the retrosplenial cortex and the overall cortex. The seizure-induced expression of c-fos and NGFI-A in thalamus, hypothalamus, inferior colliculus and medical geniculate seen in vehicle- and NR1 nonsense-treated mice was completely blocked by NR1 antisense pretreatment.
Acoustic Stimulation↗
The use of in vivo fluorescence image sequences to indicate the occurrence and propagation of transient focal depolarizations in cerebral ischemia.
A method for the detection and tracking of propagated fluorescence transients as indicators of depolarizations in focal cerebral ischemia is described, together with initial results indicating the potential of the method. The cortex of the right cerebral hemisphere was exposed for nonrecovery experiments in five cats anesthetized with chloralose and subjected to permanent middle cerebral artery (MCA) occlusion. Fluorescence with 370-nm excitation (attributed to the degree of reduction of the NAD/H couple) was imaged with an intensified charge-coupled device camera and digitized. Sequences of images representing changes in gray level from a baseline image were examined, together with the time courses of mean gray levels in specified regions of interest. Spontaneous increases in fluorescence occurred, starting most commonly at the edge of areas of core ischemia; they propagated usually throughout the periinfarct zone and resolved to varying degrees and at varying rates, depending on proximity of the locus to the MCA input. When a fluorescence transient reached the anterior cerebral artery territory, its initial polarity reversed from an increase to a decrease in fluorescence. An initial increase in fluorescence in response to the arrival of a transient may characterize cortex that will become infarcted, if pathophysiological changes in the periinfarct zone are allowed to evolve naturally.
Animals↗
Anticonvulsant effects of 7-nitroindazole in rodents with reflex epilepsy may result from L-arginine accumulation or a reduction in nitric oxide or L-citrulline formation.
1. To investigate the role of nitric oxide in epilepsy we have studied the effects of agents which affect nitric oxide synthesis in sound-induced seizures in DBA/2 mice and in genetically epilepsy-prone (GEP) rats. 2. The neuronal selective nitric oxide synthase inhibitor, 7-nitroindazole (7-NI) is anticonvulsant in these models with ED50 values against clonic seizures in mg kg-1 i.p. (times following injection) of: 74 (+0.25 h), 120 (+1 h) in DAB/2 mice, and 56 (+0.25 h), 42 (+0.5 h), 36 (+1 h), 28 (+2 h), 38 (+4 h), 93 (+8 h) in GEP rats. 3. Therapeutic indices (locomotor deficit ED50/anticonvulsant ED50) for 7-NI are low, ranging from 0.6 to 1.1 at +0.25 h to +1 h after administration in GEP rats, but are more favourable at later times (1.6 at +2 h and 2.9 at +4 h). 4. The substrate for nitric oxide synthase, L-arginine (500-5000 mg kg-1, i.p. or 100-300 micrograms, i.c.v.) but not D-arginine (300 micrograms i.c.v.) is anticonvulsant in DBA/2 mice. L-Arginine (500-5000 mg kg-1, i.p. or 1800-6000 micrograms, i.c.v.) is a more potent anticonvulsant than D-arginine (1500-2500 mg kg-1, i.p. or 6000 micrograms, i.c.v.) in GEP rats. 5. In DBA/2 mice, L-arginine (30 micrograms i.c.v.) reverses the anticonvulsant effect of 7-NI (50 mg kg-1, i.p.). 6. In GEP rats, low dose L-arginine (25-50 mg kg-1, i.p.) but not D-arginine (50 mg kg-1, i.p.) reverses the anticonvulsant effect of low dose 7-NI (25 mg kg-1, i.p.). A higher dose of L-arginine (500 mg kg-1, i.p.) or 7-NI (50 mg kg-1, i.p.) produces summation of anticonvulsant effect. 7. The product for nitric oxide synthase, L-citrulline (250-831 micrograms i.c.v.), is convulsant in DBA/2 mice. 8. The anticonvulsant effect of the neuronal selective nitric oxide synthase inhibitor, 7-nitroindazole, may therefore be mediated by L-arginine accumulation, as well as by a reduction in nitric oxide and L-citrulline formation in rodent models of reflex epilepsy.
Animals↗
Update on the mechanism of action of antiepileptic drugs.
Novel antiepileptic drugs (AEDs) are thought to act on voltage-sensitive ion channels, on inhibitory neurotransmission or on excitatory neurotransmission. Two successful examples of rational AED design that potentiate GABA-mediated inhibition are vigabatrin (VGB) by irreversible inhibition of GABA-transaminase, and tiagabine (TGB) by blocking GABA uptake. Lamotrigine (LTG) prolongs inactivation of voltage-dependent sodium channels. The anticonvulsant action of remacemide (RCM) is probably largely due to blockade of NMDA receptors and prolonged inactivation of sodium channels induced by its desglycinated metabolite. Felbamate (FBM) apparently blocks NMDA receptors, potentiates GABA-mediated responses, blocks L-type calcium channels, and possibly also prolongs sodium channel inactivation. Similarly, topiramate (TPM) has multiple probable sites of action, including sodium channels, GABA receptors, and glutamate (AMPA) receptors. Gabapentin (GBP) apparently has a completely novel type of action, probably involving potentiation of GABA-mediated inhibition and possibly also inactivation of sodium channels. The therapeutic advantages of the novel AEDs are as yet only partially explained by our present understanding of their mechanisms of action.
4-Aminobutyrate Transaminase↗
Excitotoxicity in ALS.
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Amyotrophic Lateral Sclerosis↗